Alagille syndrome is a rare genetic disorder that affects multiple systems in the body. The five major signs and symptoms associated with Alagille syndrome are problems with the bile ducts, which carry bile from the liver to the gallbladder and small intestine to help digest fats, narrowing of the main artery from the heart to the lungs, abnormal vertebrae, eye problems, and characteristic facial features. People with three of these five main signs are considered to have the syndrome. Additional signs and symptoms may involve the veins, bones, ears, pancreas, kidney, and intestine. Symptoms may vary widely among patients, even among members of the same family.

Alagille syndrome is caused by mutations or defects in the JAG1 and NOTCH2 genes. Mutations in the JAG1 gene cause the majority of cases, while mutations in the NOTCH2 gene cause fewer than 1% of cases. These genes provide the instructions for making proteins that play a role in communication between cells during fetal development. The mutations disrupt this communication and cause errors in development.

Alagille syndrome is inherited, or passed down from parent to child. The syndrome follows an autosomal dominant pattern of inheritance, meaning that only one copy of the defective gene is necessary for the disease to appear. There are about 226 genetic mutations, or abnormalities, associated with Alagille syndrome. About 70% of cases of Alagille syndrome are associated with known mutations. About 30% of cases of Alagille syndrome, however, have unknown causes. In about 30-50% of cases of Alagille syndrome, a person inherits the disorder from a parent. The remaining cases appear to result from a spontaneous mutation in the egg or sperm cells or in the developing embryo.

The incidence of Alagille syndrome is estimated to be about one in 70,000 live births worldwide. Some researchers state that the incidence may be higher due to unreported cases of the disease. Others estimate that the prevalence may be as high as one in 20,000 live births. Alagille syndrome appears to affect males and females in equal numbers. No particular race or ethnic group appears to be affected more than any other.

People are often diagnosed with Alagille syndrome early in life, when symptoms are first apparent. About 10% of people with Alagille syndrome die from complications of the disease. This may be caused by severe heart or liver disease early in life, or by heart attack or stroke later in life.

There is no cure for Alagille syndrome. Treatment focuses on reduction of symptoms and prevention and management of complications. If managed properly, most people with Alagille syndrome can have normal life spans.

General: If symptoms of Alagille syndrome are severe, they may be detected early in life (often by six months of age or younger). Less severe forms of the disease may not be detected until adulthood. Symptoms are extremely variable, even among people with Alagille syndrome who are members of the same family. Many people with Alagille syndrome have poor growth and developmental delays.

Cognitive: People with Alagille syndrome may have mild-to-moderate intellectual disability. Researchers typically use intelligence quotient (IQ) tests to measure the severity of a person's intellectual disabilities. Individuals who have IQs of 85-115 are considered to have average intelligence.

People with mild intellectual disabilities have IQs of 52-69. From birth to age six, these individuals are able to develop normal social and communication skills, but motor coordination is slightly impaired. By late adolescence, they are able to learn up to about a sixth-grade level and are generally able to learn age-appropriate social skills. Adults with mild intellectual disabilities are usually able to work and support themselves, although some may need help during times of social or financial stress.

People with moderate intellectual disabilities have IQs of 36-51. Children younger than six years of age are able to talk or communicate with others, but social awareness is generally poor. Motor coordination is typically fair. Adolescents are able to learn some occupational and social skills. For instance, they may be able to learn how to travel alone in familiar places. Adults may be able to support themselves with a job but usually require guidance and assistance during times of social or financial stress.

People with severe intellectual disabilities have IQs of 20-35. Young children can say a few words, but their speech is limited. Motor coordination is generally poor. Adolescents can usually talk or communicate with others and are able to learn simple tasks. Adults typically require lifelong assistance and guidance with daily activities.

People with profound intellectual disabilities have IQs of 19 or lower. Children younger than six years old have very little motor coordination and may require nursing care. Adolescents typically have limited motor and communication skills. Adults usually require lifelong nursing care.

Eye: The most common eye symptom associated with Alagille syndrome is called posterior embryotoxon, a malformation of the back of the eye that occurs in about 80-90% of patients. It does not affect vision but can be helpful with diagnosing Alagille syndrome. Other eye symptoms may include changes in the iris and retina, which can be detected with an ophthalmologic exam. The eyes may also be jaundiced (have a yellowish tinge) caused by chronic liver problems.

Face: Distinctive facial features seen in patients with Alagille syndrome include a prominent and broad forehead, deep- and wide-set eyes, a straight nose with a bulbous tip, and a small pointed chin. The face appears as an inverted triangle.

Heart: About 90-97% of people with Alagille syndrome have heart problems. These often include poor circulation of blood from the heart to the lungs, caused by a narrowing of the blood vessels. About 7-16% of people with Alagille syndrome also have tetralogy of Fallot, which is a hole between the lower ventricles, or compartments, of the heart, and blockage of the right ventricle. Tetralogy of Fallot may be indicated by a bluish tinge to the skin, lips, and nail beds. Additional heart symptoms may include heart murmur (an extra or unusual sound during a heartbeat), a hole in the heart muscle wall that separates the atria, or upper compartments, of the heart, and narrowing or malformation of the aorta, the largest blood vessel in the body.

Liver: Liver-related symptoms observed in patients with Alagille syndrome include enlarged liver, which may not cause symptoms but may cause pain or tenderness, jaundice (yellowish discoloration) of the skin and the whites of the eyes (caused by liver problems), cholestasis (the inability of bile to flow normally from the liver to the small intestine), and liver failure. Cholestasis may cause deficiencies in the fat-soluble vitamins, A, D, E, and K. About 15% of people with Alagille syndrome will progress to cirrhosis, or excessive scarring of the liver, and liver failure. The only treatment for liver problems this severe is transplantation.

Skeleton: A characteristic feature of Alagille syndrome is the butterfly shape of the vertebrae, or the bones that make up the spinal column. This reportedly occurs in 30-90% of cases and does not usually cause any symptoms. Bones in the ribs and hands may also be affected (e.g., they may be shorter than normal).

Skin: Liver problems may cause the skin may develop a yellowish tinge (jaundice). Additional common skin symptoms may include itching and xanthomas (cholesterol deposits under the surface of the skin), which do not generally cause any symptoms.

Other: Other symptoms that may be observed in people with Alagille syndrome include pancreatic problems, delayed puberty, a high-pitched voice, very flexible finger joints, skull problems, an enlarged spleen, issues with kidney structure and function, and blood vessel problems.

General: Most children with Alagille syndrome are evaluated for liver or heart problems by six months of age. Sometimes, family members with less severe symptoms may be diagnosed after a family member with a more severe form of the disease is diagnosed. Diagnosis of Alagille syndrome may be difficult, because of the wide variability of symptoms.

The five major symptoms associated with Alagille syndrome are chronic problems with the bile ducts, narrowing of the main artery from the heart to the lungs, abnormal vertebrae, eye problems, and distinctive facial features. People with three of these five main symptoms are considered to have the syndrome. After diagnosis of Alagille syndrome, patients should be regularly followed by a gastroenterologist, cardiologist, ophthalmologist, and kidney specialist.

Blood tests: A sample of blood may be drawn to measure levels of the fat-soluble vitamins A, D, E, and K. Inadequate bile in patients with Alagille may cause reduced absorption of fat-soluble vitamins, resulting in decreased levels. High levels of cholesterol and triglycerides in the blood are other common features of Alagille syndrome caused by cholestasis. Other considerations may include measurements of clotting, enzyme levels, bilirubin, bile acids, and anemia.

Echocardiogram: An echocardiogram, which uses sound waves to create a moving picture of the heart, can be used to test for abnormal heart structure and function.

Eye exam: An eye exam using a special piece of equipment known as a slit lamp may be used to provide a magnified, three-dimensional view of the different parts of the eye to check for abnormalities.

Genetic testing: If Alagille syndrome is suspected, a genetic test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for defects in the JAG1 or NOTCH2 genes. If these are detected, a positive diagnosis is made.

Imaging studies: Ultrasound uses sound waves to create pictures of the structures inside the body and may be used to assess the health of the liver, kidneys, and spleen. An ultrasound done during pregnancy may be able to detect the heart problems associated with Alagille syndrome in a developing fetus. X-ray imaging may help a clinician assess the shape of the vertebrae or bones that make up the spinal column. Imaging studies can be used throughout the course of the disease to periodically assess the health and function of the blood vessels, heart, liver, and kidneys.

An endoscopic retrograde cholangiopancreatography (ERCP) is a type of imaging study that allows a clinician to assess the health and function of the liver, gallbladder, bile ducts, and pancreas. An ERCP combines the use of X-rays and an endoscope, which is a long, flexible, lighted tube that is inserted into the mouth and down the throat. Before the exam, the patient is given certain drugs (anesthetics) to numb the back of the throat and aid in relaxation. The patient then swallows the endoscope so a clinician may view the inside of the stomach and upper small intestine. Dyes may be injected through the tube so that other parts of the digestive tract, such as the pancreas and bile ducts, may be visible in an X-ray.

Liver biopsy: In a biopsy, a small sample of tissue is removed for analysis in a laboratory. In Alagille syndrome, it may be necessary to acquire a liver biopsy to assess the bile ducts. Liver biopsy findings may vary depending on the age of the patient and the stage and severity of the disease. A liver biopsy done on a newborn may not reveal findings characteristic of Alagille syndrome and may lead to misdiagnosis. Because problems with the bile ducts do not occur only in Alagille syndrome, other tests may be needed to verify the cause of this symptom.

Prenatal DNA testing: If there is a family history of Alagille syndrome, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose Alagille syndrome. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.

During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.

During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for a mutation in the JAG1 or NOTCH2 genes. Miscarriage occurs in about 0.5%-1% of women who undergo this procedure.

Heart disease: Narrowing of the blood vessels and high levels of cholesterol and triglycerides in the blood can lead to heart disease in patients with Alagille syndrome.

Kidney disease: Problems with the kidneys, including narrowing of the renal artery, having a single kidney, and structural malformations, may occur in patients with Alagille syndrome. Scarring and hardening of the blood vessels in the kidney can also lead to complications. This causes protein to be excreted in the urine and further kidney damage.

Liver: Complications that result from the inability of bile to be delivered from the liver into the small intestine include jaundice (yellowing) of the skin and whites of the eyes, cirrhosis, and liver failure.

Although the exact cause is not known, there have been several reports of hepatocellular carcinoma, a type of liver cancer, in patients with Alagille syndrome.

Skeletal: If vitamin deficiencies are not recognized, patients with Alagille syndrome may develop osteopenia, or low bone density, which increases the risk of fracture.

Vision: Although eye symptoms of Alagille syndrome do not typically affect vision, visual impairment has been observed in patients with intracranial hypertension high blood pressure in the brain).

Other: Other complications that may be seen in Alagille syndrome include anemia (low levels of red blood cells), bleeding in the brain, and severe itching of the skin.

General: There is no cure for Alagille syndrome. Treatment focuses on the relief of symptoms and the prevention and management of complications. Treatment strategies for people with Alagille syndrome should include the expertise of a geneticist, physician, gastroenterologist, nutritionist, cardiologist, ophthalmologist, and liver transplant specialist. Growth should be monitored using standard growth charts, and nutritional intake should be modified based on this information.

Diet: People with Alagille syndrome tend to absorb nutrients better when the diet is higher in carbohydrates and medium-chain triglycerides. Patients who are underweight may benefit from high-calorie supplements or overnight tube feeding. In addition, patients should receive supplementation with the fat-soluble vitamins A, D, E, and K. Zinc supplementation may also be necessary in some patients.

Drugs: Most medications used in Alagille syndrome treat the discomfort associated with itching of the skin. Drugs that stimulate bile, such as ursodeoxycholic acid (Actigall®), can help treat the symptoms of itching and cholesterol deposits under the skin. Rifampin (Rifadin®, Rimactane®) and antihistamines such as hydroxyzine (Atarax®, Vistaril®) and diphenhydramine may also help with itching. Liver function should be closely monitored in patients taking rifampin, because of the potential for liver damage.

Cholesterol-lowering medications such as cholestyramine (Questran®) can be used in patients with high blood cholesterol levels. These medications may worsen fat-soluble vitamin deficiencies, however, and should be used with caution in patients with Alagille syndrome. Prescription-strength versions of the fat-soluble vitamins A, D, E, and K and minerals such as zinc may also be prescribed.

All patients with Alagille syndrome, except those with narrowing of the artery to the lungs, should also receive antibiotics that protect against an infection of the heart called subacute bacterial endocarditis.

Liver transplantation: Patients with Alagille syndrome with severe liver disease may benefit from liver transplantation. Liver transplantation should be considered if a patient has progressively worsening liver function, high blood pressure in the main vein leading from the liver to the heart, failure to thrive in infants, and severe itching that does not respond to other treatments. Liver transplantation is a complex procedure that may be associated with several complications, including organ rejection. About 80% of people who have successful liver transplants survive for five years after the procedure. Improved liver function and some catch-up growth may be observed in these patients.

Occupational therapy: Patients with Alagille syndrome may benefit from occupational therapy. During sessions, a therapist helps the child learn skills to help him or her perform basic daily tasks, such as eating, dressing, and communicating with others. Parents and caregivers can ask their children's pediatricians to recommend a therapist.

Spleen guard: Patients with an enlarged spleen should wear a padded spleen guard to protect the organ and surrounding areas from traumatic injury.

Surgery: A procedure called biliary diversion, in which a connection is made between the gallbladder and the skin so that bile may be drained to the outside of the body, may help reduce the severe itching that some patients experience. Patients with more severe forms of Alagille syndrome may require heart surgery to correct structural and functional problems in the heart.

Vaccinations: Vaccinations for hepatitis B, hepatitis A, and Pneumovax may decrease the risk of complications from chronic liver disease.

Other: Individuals with severe heart disease are often advised to avoid physical activity. Individuals with an enlarged spleen should avoid rough contact sports such as football. Individuals with liver disease should avoid alcohol consumption.

Note: Currently there is a lack of scientific evidence on the use of integrative therapies for the treatment or prevention of Alagille syndrome. The therapies listed below have been studied for related conditions, such as fat-soluble vitamin deficiency.

Unclear or conflicting scientific evidence:

ADEKs®: ADEKs® is a multivitamin with minerals, mainly consisting of vitamins A, D, E, and K. Vitamin C, B-complex vitamins, folic acid, and zinc are also found in this supplement. ADEKs® may be given to increase these necessary nutrients along with the pancreatic enzymes. This preparation uses high doses of the fat-soluble vitamins (A, D, E, and K) in a water-miscible form. It is available as liquid, drops, and tablet that must be chewed or crushed before swallowing. Patients should speak with their doctors before taking any supplementation, especially before taking ADEKs®. Recommended doses should not be exceeded, because of the risk of toxicity. Pregnant women and patients taking anticoagulant therapy should use ADEKs with caution.

General: Because Alagille syndrome is inherited, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with a family history of Alagille syndrome.

Genetic testing and counseling: Individuals who have Alagille syndrome may meet with a genetic counselor to discuss the risks of having children with the disease. Individuals with a family history of Alagille syndrome, but who have not been diagnosed with the syndrome themselves, may meet with a genetic counselor to determine whether they carry the defective JAG1 or NOTCH2 genes.

If an individual who has not yet been diagnosed with Alagille syndrome is found to possess one of the defective genes, he or she may undergo genetic counseling before conceiving a child. Genetic counselors can explain the options and the associated risks of various tests, including preimplantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).

During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.

During CVS, a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for a mutation in the JAG1 or NOTCH2 genes. Miscarriage occurs in about 0.5%-1% of women who undergo this procedure.

Preimplantation genetic diagnosis (PGD) may be used with in vitro, artificial fertilization. In PGD, embryos are tested for defective JAG1 or NOTCH2 genes, and only the embryos that are not affected are chosen to be implanted. Because Alagille syndrome can be detected in a fetus, parents may choose whether or not to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.

General: Alagille is a rare, inherited genetic disorder caused by mutations or defects in the JAG1 and NOTCH2 genes. Mutations in the JAG1 gene cause the majority of cases, while mutations in the NOTCH2 gene cause fewer than 1% of cases. There are about 226 different types of genetic mutations in these genes that are associated with Alagille syndrome. About 70% of cases of Alagille syndrome are associated with known mutations. About 30% of cases of Alagille syndrome, however, have unknown causes.

Inheritance: In about 30-50% of cases of Alagille syndrome, a person inherits the disorder from a parent. When inherited, the syndrome follows an autosomal dominant pattern of inheritance. Individuals receive two copies of most genes, one from the mother and one from the father. For a person to inherit a dominant disorder, only one copy of the disease-causing gene is necessary. If one parent has the disorder, there is a 50% chance that the child will have the disorder. If both parents have the disorder, there is a 75% chance that the child will have the disorder.

Random occurrence: About 50-70% of cases of Alagille syndrome occur in individuals with no family history of the disease. These cases are caused by a spontaneous mutation in the egg or sperm cells, or in the developing embryo. These individuals can pass the disorder on to their children.

Because Alagille syndrome is inherited, a family history of the disease is the only known risk factor. In about 30-50% of cases of Alagille syndrome, a person inherits the disorder from a parent. The remainder of cases appears to result from a spontaneous mutation in the egg or sperm cells or in the developing embryo. A child of a person with Alagille syndrome has about a 50% chance of inheriting the disorder.

The incidence of Alagille syndrome is estimated to be about one in 70,000 live births. Some researchers believe that the incidence may be higher because of unreported cases of the disease. Others estimate that the prevalence may be as high as one in 20,000 live births. Alagille syndrome appears to affect males and females in equal numbers. No particular race or ethnic group appears to be affected more than any other.

The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.